Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases

Magnus S. Alphey, Janine Konig, Alan H. Fairlamb

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)


    TbTDPX (Trypanosoma brucei tryparedoxin-dependent peroxidase) is a genetically validated drug target in the fight against African sleeping sickness. Despite its similarity to members of the GPX (glutathione peroxidase) family, TbTDPX2 is functional as a monomer, lacks a selenocysteine residue and relies instead on peroxidatic and resolving cysteine residues for catalysis and uses tryparedoxin rather than glutathione as electron donor. Kinetic studies indicate a saturable Ping Pong mechanism, unlike selenium-dependent GPXs, which display infinite K-m and V-max values. The structure of the reduced enzyme at 2.1 angstrom (0.21 nm) resolution reveals that the catalytic thiol groups are widely separated [19 angstrom (0.19 nm)] and thus unable to form a disulphide bond without a large conformational change in the secondary-structure architecture, as reported for certain plant GPXs. A model of the oxidized enzyme structure is presented and the implications for small-molecule inhibition are discussed.

    Original languageEnglish
    Pages (from-to)375-381
    Number of pages7
    JournalBiochemical Journal
    Issue number3
    Publication statusPublished - 15 Sept 2008


    • dithiol-dependent peroxidase
    • drug discovery
    • glutathione peroxidase
    • Leishmania
    • Trypanosoma
    • trypanothione
    • BRUCEI
    • MODEL
    • FOLD


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